CA2138538A1 - Production and use of imines of porphyrins - Google Patents

Production and use of imines of porphyrins


Publication number
CA2138538A1 CA 2138538 CA2138538A CA2138538A1 CA 2138538 A1 CA2138538 A1 CA 2138538A1 CA 2138538 CA2138538 CA 2138538 CA 2138538 A CA2138538 A CA 2138538A CA 2138538 A1 CA2138538 A1 CA 2138538A1
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CA 2138538
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French (fr)
Dimitris Skalkos
Steven H. Selman
James A. Hampton
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Medical College of Ohio
University of Toledo
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Dimitris Skalkos
Steven H. Selman
James A. Hampton
University Of Toledo (The)
Medical College Of Ohio
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Priority to US901,597 priority
Application filed by Dimitris Skalkos, Steven H. Selman, James A. Hampton, University Of Toledo (The), Medical College Of Ohio filed Critical Dimitris Skalkos
Publication of CA2138538A1 publication Critical patent/CA2138538A1/en
Application status is Abandoned legal-status Critical



    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/22Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/555Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol


Purified imines of porphyrins, chlorins, bacteriochlorins, chlorophylls, bacteriochlorophylls, purpurins, reduced purpurins, verdins, Diels Alder adducts, benzochlorins and metal complexes of the foregoing imines are disclosed. The formulas of the ben-zochlorinimines and of the benzochlorinimine metal complexes are set forth (1) and (2). In specific examples, M in the metal complexes is a copper cation that is complexed with two of the nitrogens of the benzochlorinimine R' and R"" are methyl, and R1 through R8 are ethyl.


2 i ~ ~ 5 3 8 PCT`/US93/05727 TITLE

Production and use of imines of porphyrins This invenlion rclales lo lllc production and use of imines of porphyrins of porpllyrins and of relaled compounds including mctal complexes e.g. bcnzoclllorinimines alld bcnzochloriniminc mclal complcxcs whicll arc uscful in pholodyl1amic lhcrapy. Thc in enlion also rclalcs to composiiions conlaining such imincs. Spccific c~c;lmpics of Ihc bcn~ochloril1intincs antl Or lltc bcnzochlorinimine melal 10 complcxcs of lllc inven~ion havc Ihc following structurcs:

CH3 CH 2 ~ CH3 CH 2 ~
~ ~ CH2CH3 ~ CH2C113 el- 3 c~ 2 ~ ~ CH 3 t H z ~
~ N H~/ ~12 CH J ~ N .~,/ `C H 2 CH 3 ~ ~ CH3 A ~ CH: N~

N HN--\ / N
CH l CH 2 ~ ~CH 2CH3 CH3 CH 2 ~ CH 2 CH 3 CH3CH2 H2CH3 t',H~CH2 H2CH~
Forrnul~ I Fomtula 11 where M compriscs a me~al ca~ion ~ha~ is complcxed wilh ~wo of tllC nilrogens of the benzoclllorin and is Ag Al Ce Co G Cu Dy Er Eu Fe Ga Gd Hf Ho ~n La Lu Mn Mo Nd Ni Pb Pd Pr Pt 25 Rh Sb Sc Sm Sn Tb ~Tc Th Ti Tl Tm U V Y Yb Zn or Zr and A is a physiologically acceplal)le anion e.g. chloride.
The benzochlorins benzochlorin mclal complexes and 'IIC othcr imines and imil1e me~al comp]exes according ~o the ins~ant invenlion are pho~o; i.e. excitation at a sui~able wavelength promotes them to lhe sing~et state from which they decay to tl1e ground slate primarily by non-radiative patbways 30 releasing ~heir energy in several forms including heat eleclron transfer and probably forming at least one active oxygen species frce radicals or bo~ urther when tl1cy are suilably a-lminist~red for example hll.avcnously to a livh1g palient llley are rcjecled by healll1y ti.ssue bul nol by lumors and as a ~onx l.l a~c- tlley are still present a suitable timc aflcr ~minictralion~ in lumors of llle palient to whom ~hey were atdministered but are no longer prcsent in adjtcellt heallhy tissuc so that they can be 35 promoted to the singlel state by excitemen( al a suilable wavelength and will thcn destroy the tumor as they decay to the ground stale. Photolllermal sensitizers whicll deslroy tumors by the release of heal afler they have been prontoted to tlle singlel slale arc discl~scd by Jori G. el al. Journ~ll of Pl~orocilemis~ry WO 94/00118 ' PCr/US93/05727 and P~tobiology, B: Biolof~, fi (1990) pagcs 93-101. Scnsiti7crs Ihat after thcy havc bccn promotcd to~
singlct state produce activc oxygcn spccics prohablY inciuding singlct oxygcn which ~hcn dcstrovs tumors arc also known bcing discloscd for c:camplc in "Morgan ct .~h 1" U.S. patcnt No. 4 988 808 lanuary 29 1991 and in rcfcrenccs citcd therein.

Bcnzochlorin mctal complcxcs and bcn70chlorins having ~hc formulas of Figs. 1 and 2 bclow arc discloscd in Morgan ct al. I:

R~ ¦ jPA ,." ~ ~ 'A4 15R10~ jM ~ R12R10~ ~R12 R8 ~_ >- R5R8 ~ R5 7Rl 1 ~ 7 R11 ~3 Fio- 1 F~9. 2 20 Co . pou ds having ~he :,llu~.lul~.s of Figs. 1 and 2 are also discloscd by Morgan c~ al. "Photodynamic Action of Bcnzochlorins" S~IE Vol. 1066-Pho~odynamic Thcrapy: Mech~ni~mc (1989) pages 146 et scq. and by Viccnte et al. "Vilsmcicr Rcactions of rO.~ I y,i s and Chlorins wi~h 3-(Dimc~hylamino)acrolein To Give meso-(2-Fu,,,,ylvillyl)~Julyhy~ '" J. Org. Cflcm. 1991 56 pagcs 4407-4418 (see also Arnold D.P.
ct al. Journal of 7he Cllemical 50cic(y, I'crkin Transact~ons 1(1979) pages 1660 et scq.). The specific 25 bcnzochlorins Aicrloscd by Morgan e~ al. are c~ ..pou .ds where cach of Rl tllrough R8 is etllyl cach of R10 through R12 is hydrogcn and (a) thc ~u pou~d h~s thc structurc Or Fig. 1 R14 is SO3Na and M is Sn;
(b) thc ~u~ ~I cund thc structurc of Fig. 2 and R14 is H;
(c) thc ~u~puul~d has thc structurc of Fig. 2 and R14 is SO3Na; and (d) the ~ù pu-- d has d~c s~ruc~urc of Fig. 1 R14 is H and M is Sn.
Similarly pollJllylill: chlorins bacterioclllorins chlorophylls bactcriochlorophylls y~lllJulhl: reduced yuluulhls verdins Diels-Alder Adducts isobac~eriochlorins and metal cûmplexes of the foregoing arc all known as is the usc of ~he Yilsmcicr rcagcn~ ~o introduce formyl groups in~o yOIy}lyli~ he reac~ion of ~he Vilsmeier reagent (dilnc~hylfonnamidc for cxamplc and phosphoryl chloridc) produccs imh1es as 3 5 in~crml~Ai~trc So far as is known howcvcr ~hc imincs produced by ~hc Vilsmeicr rcagcn~ have no~ prcviously been sep~r~rd from thc rcac~ion mixturc; ins~cad ~hc reaction has been allowcd lo procccd until thc formyl group was formed.

The prcsen~ invention is a family of imhtes, e g, bcnzochlorinimincs having ~he struclure set forth below and identiried by Iegend, and a family of imine melal complexes, e g, benzochlorinimine mctal complexcs having lhe structure set forth below all~l idcl1(iricd by Iegend, and a mclhod ror treating tumors which involve~s 5 the administration of one of ~he imhlc~s, e g, a benzochlorinimine having thc structure set forth bclow, or one of the iminc metal complexes, e g, a ben70chlorinimine metal complex having t}-e strueture set forth below, (o a human or animal patient with a tumor, an(l, after a suitable pcriod of time, irradiation of thc tumor with light of a suitablc wavelengtl1 and Or sufficient intensity to promote the imine or imine metal complex to the singlet state ~<R4 <\ ~ , R A ~ CH

NHN ~ N~--\
R8 ~ ~R5 \\

~ ~n ~ ~
llo~ corn~ox In thc ben7.0ehlorinimines and bcn70ehlorinil11iIlc metal complexes having the foregoing formulas:
M and A havo thc m-~ningS indiealed above, R' and R" ean bc the same or diffcrent and eaeh is l,ydlub~,", an alkyl group having from 1 to 4 earbon atoms, or ~hc two, tog~her, can eonsist of two CH2 groups caeh of whieh is bonded to ~hc nilrogcn atom, and the two of whieh are a part of an aliphatic hydrocarbon 25 ehain having from 4 to 6 earbon atoms, and caeh of R1 through R8 and R11 is H or CHO, an alkyl group othcr than t-butyl having rrom I to 4 carbon atoms, an alkylenc group having from 2 to 4 earbon atoms, a group having thc formula R3N(R4)2 whcrc R3 is a biva}cnt aliphatie hyd,oc..~l~on radical having from 30 1 to 4 carbon atoms, wherein any Garbon to earbon bond is cithcr a single or a double bond, and not more than one is a double bond; R4 is Lydlugc.l or an alkyl radiGal having from 1 to 2 earbon atoms and the two R4 groups Gan be the same or differen~, a group having the formula R~N(R5)~ A whcrc R3 is a bivalcnl aliphatie hydlucallJoll radieal having from 1 to 4 earbon atoms, whcrcin any carbon to earbon bond is cithcr a single or a doublc bond, and not more than 35 one is a doublc bond; A is a physiologieally ~rcept~ble anion and R5 is an alkyl group having from 1 to 2 earbon aloms and the three Rs groups Gan be the same or different, a group having the formula R30H where R3 is a bivalent aliphalic hydluc.~llJon radical having from 1 to 4 Garbon atoms, wherein any carbon to earbon bond is cither a single or a doub}e bond, and not more than one is a doub}e bond, or WO 94/00118 2~ 38538 PCr/US93/05727 CO2R', CH2CO2R' or CH2CH2C02R' uhcrc R' is H, or an aikyl ~roup o~hcr than t-butyl having ~--onc lo four carbon atoms, with thc proviso that R11 can bc S03ii or a salt thcrcof.
Othcr in~incs an~i iminc mc~al complcxc~s of thc ramilics of thc instant invcntion havc thc ~ormulas sct 5 forth bclow, and idcntificd by Icgcnd.

R1~ R4 R1~R4 '~ NH N ~< ~R~ NH N ~< ,r~

~>-CH~N. ~~CH~N~r, /--N HN ~\ ~--N HN ~\
R8~ .~ R5 R8~ 4~ R5 R7 r~ .Rl R6 R7 Chlorlnlmh~ R6 _ N

Chlorophylllmlne Bacteriochlorophyllimine I

~'~~ R2 R3 A- R~ < R4 /--N HN ~\ /~--N HN ~\
~ RS R~ ~

Bar~eriochlorphylllmlne 11 Bacterio~ h~lllmlne 111 WO 94/00118 2 1 3 8~5 3 8~ PCI/US93J05727 9 10 ~- R'~
~ f~=~1o R~ R ~¦ \R~

\ />--N HN--\
R~ R~ _~R6 7 ~ 7 5 Purpurinimine I Purpurlnlmlne 11 /~~ N H~l R9 ~ R5 R8 ~ R5 R7 R~l R R5 Verdlnlmlne I Verdinimine 11 E~9 ~10 R1 ~ ~R~ R ¦ R~
R.~N: CH-6 ~ 6 ~ N~

/--N H~ N HN
F18 ~_~5 R~ R

Verdinimine 111 Reduced Purpurinimine WO 94/00118 2 1 3 85 3 8 PCl/US93/05727 CO2R11 CO2R11 CO2R11 C~O2R11 R1~ r ~ R1 ~~ ~$ CH ;~

~--N H N ~ N H N--\
R8~ R5 R8~1 R5 ~7 R6 R7 R6 Dlels Alder Adduct Imine I Diels Alder Adduct Imine 11 CO~CO2R A- R' ~ CO~OzR

R1~ R1 ~

~-- ~ CH= ¦~ R~
/~--H HN~ H HN~
R8~R5 R8~R5 h7 R6 h7 R6 Diels Alder Adduct Imine 111 Diels Alder Adduct Imine IV

CO2R' CO2 R~
R2 'q R2 ,R ~ ~\

Rl $~=~3 R4~C02R ~-- N ~ ~kR4~ C0 <~ ~ CH: N

N HN--~ N HN--\
R8 ~ ~ R5 R8~_ ~R5 Dlels Alder Adduct Imine V Diels Alder Adduct Imine Vl 2 ~ ~ 8 ~3 8~ PCr/US93/05727 WO 94/001 1 8 ~ `; ./ `, . 3 l R' ,~-R2 CH-~ R3 R2 F~:~
R~ 4R~<~>R4 A- R' --NH HN ~ NH HN--\
R6R8$~--~ R6 7 B 7 El I.'K' ' ~I~II~'n' - t ~ 1~1," 'r,~ 11 C02R' C02R' ~ ~ \

R1~--~) R1~--~) R A
~ CH N ~ ~, N H N N H N
R~_~R5 R~ R5 B~ le-in DlelsAlderAdduct A- R'~
ImlneI i~c~ iuuillulll~ DlelsAiderAddur,t Imlne 11 COzR' qO2R' C02R q 2 \0~ A- R~ + \~
R2 R3 / ~ R2 R~ I R3 /
A1 ~/ R1~J
~, N H N ~ ~, N H N ~
i~i= CH 6 ~ 6 ~~N HN~ ~~N HN
R~R5 R~ f ~R~

E 9 luJ Ilel ll l Dlels Aider Adduc~ rio~ii llvd u Dlels Alder Adduct Imlne lll Imine IV

WO 94/00118 2 1 3 85 3 ~ PCr/US93/05727 ~H~

7i38.,1~.ivJ.h~ 6 Ih~11 Id ~ 7 s~ ,lvc~ "l,.,~ G
Meta Complex ~ ~ C :N, ~ ~:N~

Porphyrinimine Chlo~ "ine Metal Complex Metal Complex r--~ R~R4 ? \ C:tN~

Ct~le~uiJ~ , )eBa~eriù~ ,I,yllimine I
Meta~ Complex Me~al Complex 21~85~8 WO 94tO0118 ~ r t~ ~ `' PCI/US93/05727 ? \)-R~
R~__~R5 R~_~ R6 Bacteriochlorophyllimine 11 Bacteriochlorophyiiimlne 111 Me~ai Complex Me~l Complsx R9 R10 A- R' /=\ .~N:5 ~10 ~ ~ ~ i Purpurinimine 1 7 Purpurinimine Me~al Complex Melai Complex ~ ~ \ R ~
F~ R5 R8 R5 R7 Rll A- R,~N CH R~
VetLii"~ e I Ver~lii,i"~i"e 11 Metal Complex Metal Complex WO 94/00118 213 8 5 38 ; PCr/US93/05727 A- R'~ < ~, A-R7 5 Fl Fl5 Verdi,~i",ine 111 Reduced PurpurinimTne Motal Complox Metal Compl~x C02R~ C02R~ co2R' S2R

R1 ~ ) R1 ~T~) ~ \ ~CH N~R A
R~_~R5 R~ R5 Diels Alder Adduct Imine IDiels Alder Adduct Imine 11 Metal Complex Metal Complex COzR~ C02R~ CO 2R~ CO2R~

R A- ~ ) R8 R5 Rs R5 h7 R~ h7 R~
DielsAlderAdductlmine 111 DielsAlderAdductlmine IV
Metal Complex Metal Complex WO 94/001 18 2 1 3 ~ $ ~,8 ~t ~ PCr/US93/05727 Co2R' CCs2 R' R2 ~-- R2 CH= N /
Fff ~ Cl~

RB ~ R5 R8 R5 Dlels Alder Adduct Imlne VDlels Alder Adduct Imine Vl Metal Complex Metal Complex +,~ A

R1-< ll ¦ > R4R1 < ll ¦ > F14 \ N t~i ~/ , . \ ~ N ~/
~ R' R~_ ~ R~ R8~, ~> R~i Met~l Complex Metat Complex C~o2R~ C~
R2 R3 / ~ R2 R3/

~SCH-N~ ~

R R5 R~ R5 R6 N= CH R6 lu~il1 Diels AlderAdduct A- R~
Imine I Metsl Complex Irnlne 11 Metsl Complex WO 94/OOt 18 ~ i 3 ~ 5 3 8 PCI`/US93/05727 C02R~ ço2R Co2R' q2R' A~
p~ R~ R

Bal,l.,rlv~l,lu,l" Dlels ~Udor Adduct B~_t~ ,ll" Dlcl~ Alde~ Aoduct Imlno lll Mctsl Complex Imlne IV Metsl Complox In the foregoing formulas, M co"~pliscs a mctal ca~ion tha~ is complexcd with lwo of lhc nilrogens of the benzochlorin and is Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fc, Ga, Gd, Hf, Ho, In, La, Lu, Mn, Mo, Nd, Ni, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, 9~nrrc, Th, Ti, Tl, Tm, U, V, Y, Yb, Zn or Zr, A i5 a physiologically acccptablc anion, c.g., chloridc, R' and R" can be thc same or differcnt and each is h~dlugc~, an alkyl group having from 1 to 4 carbon atoms, ~or the ~wo, togcthcr, can consist of two CH2 groups cach of which is bonded to the nitrogcn atom, and the lwo of which are a part of an aliphatic hyJ~u~ bo chain having ~rom 4 lo 6 Garbon aloms, and each of RI through R11 is H or CHO, an alkyl group othcr than t-butyl having from 1 to 4 carbon atoms, an alkylene group having from 2 to 4 carbon atoms, a group having the formula R~N(R,)2 where R3 is a bivalent aliphatic hy~hoca~llon radiGal having fiom 1 to 4 Galbon atoms, whcrein any Garbon to carbon bond is either a single or a double bond, and not more than one is a double bond; R4 is hydrogen or an alkyl radiGal having from I lo 2 Garbon atoms and the two R~
groups can bc the samc or diffcrent, a group havil~g thc formula R3N(R5)3 A whcrc R3 is a bivalcnt aliphatic hyd~o~d~von radical having from 1 to 4 carbon atoms, whcrein any carbon to Garbon bond is eithcr a singlc or a double bond, and not more than one is a double bon(l; A is a physiologiGally acceptable anion and R5 is an alkyl group having from 1 to 2 carbon atoMs and the three R5 groups can be the same or differcnt, a group having the formula R~OH wherc R3 is a bivalent aliphatic hy~lloca.l~on radical having from 1 tû
4 Garbon atoms, whercin any carbon to carbon bond is cilhcr a singlc or a double bond, and not morc than one is a double bond, or CO2R', CH2CO2R' or CH2CH2CO2R' whcrc R' is H, or an alkyl group other than t-butyl having from one to four Garbon atoms, with the proviso that Rll can bc S03H or a salt thcreof.
In thc foregoing Chlorinimincs and mctal complexcs, chhcr R3 or R4 can be a CH2 group or O which, in either G'ISC, is bondcd to thc carbon of thc pyrrolc ring by a double bond. Likewise, in thc foregoing families of v"-pv~.,ds which arc dcsignatcd Isobactcriochloriniminc I and Isobactcriochloriniminc II ci~her R1 or R2 ~VO 94~00118 2 1 3 8 5 ~ 8 ~ PCr/US93/05727 can bc a CH2 group or O which, in ci~hcr casc, is bondcd to thc carbon of ll~c pyrrolc ring by a doublc bond and, whcn eithcr Rl or R2 is a CH~ group or 0, ci(hcr R3 or R4 is also a CH2 group or O which is bondcd to rl1c carbon of thc pyrrolc ring by a doublc bond. ~inally, in thc forcgoing familic~s of coulpouuds which arc dcsignatcd bactcriochloriniminc cithcr R3 or R4 can bc a CHl group or O which, in cithcr casc, is bondcd to thc carbon Or thc pyrrolc ring by a doublc bond and, whcn cithcr R3 or R4 is a CI~ group or 0, cithcr R7 or R8 is also a CH2 group or O whicll is bondcd to thc carbon Or thc pyrrolc ring by a doublc bond.
Thc following cxamplcs constitutc thc bcst modcs prcscntly contcmplatcd by thc invcntors, but arc prcscntcd solcly to illustratc and disclosc thc invcntion, and arc not intcndcd to bc limiting.
As uscd hcrcin, and in thc appcndcd claims, thc tcrms "pcrccnl" and "parts" rcfcr to perccnt and parts by weight, unlcss othcrwisc indicatcd; g mcans gram or grams; mg means milligram or milligrams; ng mcans nnnogram or narlograms; pg mcans picogram or picograms; cm mcans ccntimctcr or ccntimetcrs; mm means millimctcr or millimctcrs; L mcans li~cr or litcrs; mL mcans millili~cr or millilitcrs; IlL mcans microlitcr or microlitcrs; ~/v mcans pcrccnt hy volumc; n~/O mcans molc pcrccnt, and cquals 100 timcs thc numbcr of moles of lhc c~,n~titu~ "t dcsignatcd in a composition dividcd by ~hc total numbcr of molcs in the composi~ion; V/~
mcans pcrccnt by volumc; W/V mcans wcight pcr unit of volumc, and is in Icrms of g/L; M mcans molar and eyuals the number of gram molcs of a solutc in onc litcr of a solution; ~lM mc tns micromolar and equals the numbcr of lldllOglnlll moles in onc litcr of a solution; mM mcans millilllnl~r and equals thc numbcr of milligram molcs of a solute in onc litcr of a solution; N mcans norrntl, and cquals thc numbcr of gram cquivalents of a solutc in onc litcr of solution; IlN mcans micronormal and cquals thc numbcr of microgram cquivalcnts of a solutc in onc litcr of solution; and mW mcans milliwatt or milliwatts. All tcll~ tulcs arc in C., unlcss othcrwisc indicatcd.
Examplc 1 dcscribcs the production of "Cu Bcn7.0chlorinimine I" (Formula Ir, supra, where M is Cu and A is Cl~). In Examplc 1, Cu Rçn70chl0riniminc 1 is produccd rrom a solution in 30 mL dichloroc~hanc of 1 mL Vilsmcicr rcagcnt and 80 mg "Cu Octacthyl Bcnzochlorin" (Viccnte ct al., supra):

/ ~ ~ \ CH 2CH3 CH3CH2-<\ X
~, N N ~< H2CH3 <~--N ~--~
CH3 CH 2 ~ ~L ~ CH 2CH3 Cu Octnethy1 ~ ~hl~

nle Vilsmcier rcagcnt was ~udu~cd by mixing 0.5 mL phosphoryl chloritic with 0.5mL dimctllyl formamide, and was thcn addcd to a solution of tllc Cu Octacthyl Ben70c}l10rin in thc dichloroethane, which solution had WO 94/00118 2 1 3 8 5 3 ~ PCr/US931057Z7 bcen hcated to a tc,~lp~,ldtul~; in (hé rangc of `oO to 65 . n~c reaction mixture was stirred for 15 minutc~a t~lllp~atulc within thc indicatcd range, and was thcn washed with dcioni7,cd water. After rernoval of the solvcnt under rcduccd prc~ssurc, Ihe crude product which rcmaincd was purificd by rccryslalli7ation &om dichlorom~thqnc/hcxanc. The yicld was 80 mg Cu Bcn70chlorinimine 1 (87 pcrcent of theory). The Cu Ben70chlnrinimin- I was idcnlificd by higit rcsolulion mass ~ .u.,,ctry; in dichlornmethqn~ solvent it has absorbance peaks in the visible spcctrum at ~.u~clL"~lhs of 386, 448, 570, 690 and 752 nm (51000, 30000, 7000, 12000, 35000).
The ~luccdu~: of Example 1 has been repcatcd, exccpt that equivalcnt amounts of othcr formamidcs were substitutcd for the dimcthylformamide to produce other copper octaethyl bcn7,0chlo-i-l;-,lil-~.s. The Çorrnqr.~ides used had the ~ormulas given in Ihe rollowing table, and produced benzochlorinimine mctal comrlexrs which had the structure previously identified by Icgcnd wherc R1 through R8 were ethyl, R11 was hydrogen, A- was chloride, M was copper, anti the imine group had the structure given in the table:
Number assigned Formula of forrn~nnidc used Formula ror imine group of to Cu 13cn7nrhIor- ben70chlorinimime metal complex inimine 1~ ~
HC-N(-CH2CH3)2 -CH-N~-CH2CH3)2 HC-N(-CH[CH3¦2)2 ~H-N(-CH2CH2CH2CH~)2 IV C -C
H -N(-CH2CH2CH2CH-3)2 H-N(-cH2cH2cH2cH~)2 H~ N/C~H2 ~3 ~CH~H2 \C H2 \CHz-- H2 ~ n vi~ro and in vivo testing of Cu ncn7orhloriniminc I was also carried out by çsl~qbli~hcd procedures. The cells used for thc in virro testing were AY-77 FANFT trqn~itinT-qI cell bladder cancer cclls attached to 28 em2 culture dishes. Cu Ben7uchlorinimine l was added to the culture dishes at four ~,ull~ dtions: 0.1, 0.25, 0.5 and 1 ~lg pcr mL and"Gemophor E" (dcfincd below) was added as a conlrol a~ g pcr mL. Four hours after the Cu rten7ochInrin 1 and "G-,-,lo~ho- E" additions, thc cells wcre washed, irradiated, in one serics of tests with a pulsed beam (750 nm) from an Alexandrite laser and, in another scrics of tests, wilh a cull~ beam tS90 nm) from a xenon arc lamp. lhe irradiated cells were then incubaled for 4 to 7 days until eolony formation oceurred. Surviving colonics wcre Ihen counled, and mcan valucs for surviving colonies were fI~t~ ...;..c-l The results, when the Alcxandritc laser was used, in tcrms of the mean numbers of surviving colonies as a funetion of the nuence of radialion in Joules pcr cm2, are s.l--l.lld-i~:d in the following table.

WO 94/00118 2 1 ~8 5~ ~ ` PCrIUS93/05727 Imine Concentration Flucnce surviving eolonies, mcan 1.0 0 550 0.5 0 772 0.25 0 850 0.1 0 898 Control 0 919 1.0 ~ 1.05 110 0.5 1.05 597 0.25 1.05 843 0.1 1.05 816 Control 1.05 832 1.0 2.1 18 0 5 2.1 ~07 0.25 2.1 756 0.1 2.1 701 Control 2.1 823 0.5 6.3 7 0.25 6.3 51 0.1 6.3 485 Control 6.3 846 0.25 10.5 2 0.1 10.5 83 Control 10.5 850 To eonduet the foregoing tesls, ~he Cu ~3rn7oehloriniminc I was dissolvcd in a w~ ,ially available non-ionic solubilizer and emulsifier obtaincd by rcacting cthylene oxide with eastor oil in a ratio of 35 molcs of ethylcne oxide pcr mole oî eastor oil, diluting the resulting solution with 1,2-ylu~/all~,diOl, and produeing an emulsion with thc resulting solution and 0.9 perecnt aqueous sodium ehloride solution. The speeific ~ ~ 'Q ~ ~ ~ ~ ' PCI'/US93/057~7 WO 94/00118 ' ~ ~ ~ --non-ionic solubilizcr used i5 available from BASF undcr the designation CREMOPHOR EL; it is composcd of fat:y acid eslcrs of polyglycols, glyccrol polyglycols, polyethylenc glycols and clhoxylated glycerol. The tcst solutions were prcparcd from 50 mg Cu Bcnzochlorinimine 1, about 1 mL warm solubili7,er (enough to dissolve tllc tcst compound), a;l~l enough 1,2-propanediol to makc a solution of thc Cu I3cnzochloriniminc 1 itl a mixcd diol/solul~ilizcr solvent containing 32.9 pcrcent solubilizer; finally, enough 0.9 pcrcent atlueous sodium chloride was addcd to makc 10 mL tcst solution so that thc rmal concentration of thc Cu 13en7,ocll1Orinimille 1 in the tcst solution was S mg pcr mL. Each tcst solution was mtde, with mechanical shaking and stirring, by dissolving the Cu l3cn7,ochlorinimine 1 hl tlle solubilizer. diluting the resulting solution with the indicatcd amount of l,2-propanediol, and adding tlle sodium cllloride solution to the diluted solution ~ control solution was also prepared ror usc witll each test solution. 'Ille control was identical with the tcst solution except that it contained no Cu 13enzochlorinimine l The results of the in vifro tcsting, when the Xcnon arc lamp was used, in tcrms of the mean numbers of sun~iving colonies AS a function of thc nucncc of radiation in Joulcs per cm2, arc ~u,....,a.i,,~d in the following table.
1mine Concen~ration Fluence surviving colonies, mcan 1.0 0 1 15 ' 05 0 841 0.25 0 942 0.1 0 905 Control 0 928 0.5 1.05 193 0.25 1.05 689 0.1 1.05 731 Con~rol 1.05 836 0.5 2.1 28 0.25 2.1 317 0.1 2 1 703 Control 2.1 795 0.25 6.3 5 0.1 6.3 ~1 Con~rol 6.3 907 ~ - 7 PCI JUS93/05727 0.l 10.5 2 Control 10.5 841 Thc in vivo tcsting was conductcd on malc Fishcr 344 rats wcighing 135 to 150 g in whom the-tr~n~rl7nt~blc FANFT ~N-[4-(5-nitro-2-ruryl)- ~-thiazolyl]ro~mamidc tumor syslcm had bccn impl ln~crl (USc of this systcm is rcportcd by Sclman, S.H., ct al., Cancer I~escarcfl, pp. 1924-1927, May, 1984.) Two tùmors wcre imrl~ntcd into thc subcu~ancous tis.suc of thc nank of cach Icst animal; whcn Ihc tcsting was carricd out, cach tumor was about 1 cm in diamctcr.
llhc Cu ~cnzochloriniminc 1 was dissolvcd in the prcviously idcnlificd non-ionic solubilizcr that i5 cu~ , ially availablc undcr thc designation CREMOPHOR EL, and tcst solutions which cnnl~ined 2 mg pcr mL Cu Benzochloriniminc I wcrc prcparcd as previously dcscribcd.
Thc tcsting involvcd injccting cach rat with a solution of thc Cu 13cnzochloriniminc 1, dosagc 3.5 mg pcr kg of body wcight or 7 mg pcr kg of body weight or with thc samc volume of the approprialc control, irradiating one of ~hc two tumors with la.scr ligh~, in some cascs, obscrving the animals over a pcriod of time and, in others, sacrificing thc animals, and (~Y~mining Ihc lumors. n~c injcctions wcrc madc via the dorsal tail vein. The irradiation of one of thc tumors occurrcd twenty four hours after cach rat was injccled whilc the othcr of the two tumors was shiclded.
Tumor tcmpcraturc and body corc tcmpcraturc wcrc monitorcd, using Ihcrlrtislors, onc placcd pcrcutaneously bcncath thc tumor and onc placcd i~ltrarcctally. Tumor tC~ dt~ was kcpt within 2 of body corc tcmpcraturc by dirccting a jct of cool air over thc tumor.
Both shc Alexandritc lascr and thc Xcnon arc lamp were used ~o irradiatc ~hc ~umors. The light in~ensity on the tumor was monitored; cach tumor rcccivcd 200 mW pcr cm2 ~360 Joule~s pcr cm~).
Twenty four hours aftcr thc irradiation, some of thc rats that had bccn injected with thc lesl solulion and onc of the rats that had becn injcctcd with thc control wcre saclificcd by an inlrawrdiac injcction of saturated aqucous polassium chloridc solution. Othcrs of the rats that had bccn injcctcd with thc tcst solution and with thc control solution wcrc obscrvcd ovcr a pcriod of limc. During thc Icsting, thc rats wcre under barbituate ~n~sthcsi7 (65 mg pcr kg body wcight).
Thc tumors from lhc sacrificcd rats wcrc cxciscd, placcd h~ 10 ,ocrcenl phosphatc~bufrcrcd forrnalin and cut into thrce scctions F~.~,r.,~ti~ to thcir long axis. Thc lumors wcre thcll ~ -.bcddcd in paraffin and cut into scaiûns fivc microns in width. Thc scctions wcrc stained with hcmatoxylin and cosin.
Histologic ex~min7~ion of thc staillcd sections (twcnty four hours aftcr a tumor was irradiatcd by either light sourcc) rcvealcd cxtcnsive nccrosis of canccr cclls in tumors of rats that had bccn injcctcd with Cu Bcn70chloriniminc, and no necrosis of tumor cclls in rats that had llccn injcctcd with Crcmophor. n~c cx~min7~ion revcalcd no nccrosis of cells of tumors that wcrc nol irradiated. Fourtccn days after irradiation, ~he irradiatcd tumors of threc of thc six rats that wcrc no~ sacrificcdhad and had bcen injccted with 7 mg Cu Bcnzochloriniminc pcr kg of body weight showcd no sign of tumor regrowth.
SKH1 hairlcss mice (fivc animals) wcrc injectcd with Cu Bcnzochloriniminc (7 mg pcr kg of body wcight), and the r~vc animals wcrc subjcctccl to light treatmcnt one day after thc injection. Onc of the anim31s WO 94/00118 PCI~/US93/05727 showed slight skin bum, whilc lhc othcr animals showed no skin damagc. This indication is impOrtal1t. beca cxtensive and prolongcd skin damagc is a commun sidc cfrcct of othcr s~ ailiG~
Thc production of Cu Bcn7.0chloriniminc I by rcaction bclwccn Cu Octactllyl Bcnzochlorin and a Vilsmcicr rcagcnt produccd from phosphoryl chloridc and dimcthyl forrnamidc is dcscribcd in Examplc 1. The structurc of Cu Octacthyl Bcn70chlorin is givcn abovc; its structurc is also that of Fig. 1, abovc, whcre Rl through R8 arc c~hyl, R10 through R12 and R14 arc l.yd.ogcl1, and M is Cu; thc rcaction introduccd a ~ub,lilu~"lt having thc formula -C~il=N~(C1~)2. This was an R10 substitucnt in thc FiB. 1 formula for Cu Octacthyl Bcnzochlorin. As has bccn slatcd above, othcr R10 subslitucnls have been introduccd, using thc Examplc 1 yluc~,lulc to rcacl Cu Octaclhyl 13cn;~ochlorin with Vilsmcicr rcagcnts from pl,o~yholyl chloride and rul... ..i~ othcr than dimcthyl forrnamidc, c.g., dicthyl formamide, diisopropyl form~mi~lç, di n-butyl ful..~ 1c, cyclic fo~ id~-s, and thc likc. In gcneral, by using diffcrent form~nni~ c, bcnzochlorins can bc yluduc~,d which havc the Formula 1I structurc cxccpt that onc of the CIi~ groups of thc R10 ~ub~ is rcplaced by an alkyl group havhlg from 2 to 4 carbon atoms or whcrc both of thc CH3 groups are so replaced;
thc two alkyl groups can be thc samc or diffcrcnt. Imincs whcrc R' is l-y-llogcn, R" is l-y-l~u~ , or both R' and R" are l-~J~u~,~,.. can also be prepared by conduclin~ the reaction betwecn Cu Octaethyl Brn7Ochlorin or the like and the Vilsmcicr reagcnt to introducc a formyl group into the molcculc (sce the sccond paragraph of Example A, infra) and then reacting the formyl group with ~mmoni~ a primary alkyl amine, or a sc~,ulldaly alkyl amine, to produce"-,~yc~ ly~ an iminc whcre R' and R" are both l-yJ-ug~n, an imine where one of R' and R" is Lrd~gc~ and thc othcr is an alkyl group, and an iminc wherc both R' and R" are alkyl groups.
In any case, thc alkyl group hns from onc to four carbons. ~s disclosed above, imines inc~b~-lin~ cyclic ~tlu.,lu,.,s can also be l~odu~,cd, e.g., whcrc R' and R" arc both CH2, each of which is bondcd to the nitrogcn atom, and thc two of which arc a part of an aliphatic hydluca,l,on chain having ~rom 4 ~o 6 carbon atoms Similarly, the ylu~,~duic of Extmplc I can be uscd to i--tlocluce -CH=N~(CH3)2 and olhcr iminc sul,slilu~ s into copper connpl~xrc of bcnzochlorins other than Cu Bcnzochlorin 1, and, gcnerally, into benzochlorin metal complexes having the structurc of Fig. 1, supra whcre Rl through R8 and M have the mc~ningc set forth above, R10 through R12 arc hydrogcn, and R14 can havc the same meaning as Rl through R8, and can also bc SO,H or a salt thcrcof. For cx;tmple, the Cu or the Ni t:omplex of octacthylben7,0chlorin, ~U--~I-u~ which have thc structurc of FiE. 1, supra, whcre Rl through R8 arc ethyl, R10, R11, R12 and R14 are h.~d~u~c.~, and M is coppcr or nickel, can be produccd fTom octac~l,ylyo.yh~ - by thc y-u-,clu-~; of Examplc A, below, and can bc rcactcd by thc procedure of E~camplc 1 lo produce a bcnzochlu~h.h~ c a~,cul~lillg to thc invention having ~hc structurc sct forth abovc whcre Rl through R8 arc cthyl, R11 is hydlu~ç~,.l, A is Cl-, and M is Cu or Ni. Thc idcnlitics of R' and R" depend upon the idcn(ity of lhe formamide used. Six intermediatcs wcre produccd in thc }~lUCt~5UlC of Example A, [I] nickcl octactl.rlpu.~,l.y.h~ [II], nickel meso-formyloctacthylpo",l.~,i." [111~ Nickel mcso-(B-ethoxy-carbonylvinyl)-octaelhylyu-~,l-y-i-l ~IV], meso-(B-ethoxyc.~ ,.,ylvi,,yl)-octacthylpu,~,l,ylill~ and[V~mc~so-(B-hydroxyvinyl)-oclac~hylpol~JI-ylill, and [Vl1 octacthylbcn7.0chlorin, in addition to [Vll] Nickel or Copper octaethylben~ochlorin, from the octacthylpolyhylill~ which has ~hc s~ruc~ure of Fig. 3, bclow, whctc, R1 ~hroug11 R8 are eîhyl, and R is hy~llu~cn. Fig~ 3 is a general folmula for porphyrins. n~c nickcl octacthylpo.~l.ylin~ tl1e nickel meso-formyloctaethylpol~ lin, thc Nickcl mcso-(13-cthoxy-carbonylvinyl)-octaethylpo.~ .ill, and thc WO 94/OOIl8 2 1 3 8 5 3 8 PCI/US~3/05727 meso-(B-hydroxymcthylvinyl)- )claethylporphyrin, all had the structure of Fig. 4, below, where R1 through R8 were ethyl. In the nickel octaethylpol~,i,yli" ~ was H; in thc meso-formyloctaethyl~ ,hr-i-l R was CHO;
in the nickel meso-(13-elhoxy-carbonylvinyl)-oclacthylpv.~,l,rlill R was CH=CHCO2CH~CH,; in Ihc meso-(~-hydroxy-melhylvinyl)-octaelhylporphyrin R was CH=CHCH2OH. Fig. 4 is a general structure for nickel complexe~s of porphyrins.

Rt ~ R4 ~ F14 R7 Fi~l. 3 R6 R7 Fi~. 4 RB

The nickel octa~hylpo~ lyl;ll is first produced from 100 mg nickel acetate and a solution of 20 mg octaethylpu~yl~ylil, in a mixed solvent ~o"",vs- l of 15 mL dichloromethane and S mL mcth ~nnl.
Example A
Production of Nickel octa~ lpulvllrlill Thc nickel acetate is added to the octaethrlyu"vllylill solution; the mixture which rcsults is refluxed for about 24 hours until ~he clcetronic spcelrum of the reaetion mixturc indieates that ehcla~ion is complete. The reaetion mixture is thcn COll. c.,tldlcd to 7 mL and allowed to cool to room t~ ldlUlt: of about 22. Product which ~ ip;ldles is reeovercd by fil~ra~ion, dissolvcd in a mixcd solvent c~J~ ~-u~.d of S mL dichloromc~hane and 2 mL m-th~nnl and reerystallizcd, yiclding Ni oc~ae~hylyvl~7n ~u~ ,tivi~ of nickel mcso-fnnTwloctaC~h~Ylvolvll~
Nickel meso-formyloctacthylpvll~hyl;ll is produccd (Grigg, R. et al.,J. C~lcm. SocR'ctkin Tr~ns 1,1972, pagcs 1789-1799) from a solution of 200 mg nickel meso-octactl.rlp~,lynylhl in 150 mL 1,2-dichloroethanc WO 94/00118 2 1 ~ 8 5 3 8 , PCr/US93/05727~
and 4.8 snL of a solution of phosphoryl chloridc in dimcthvlrormamidc prcparcd by making a dropwise ad of 13.7 mL frcshlY distillcd phos?horyl chloridc to 10 mL dry dimcthylforn1amidc Ihal has bccn coolcd on an icc bath and kceping lilc solution at room tcmpcraturc of about 22 for 30 minutcs~ Thc 4.8 mL porlion of the phosphoryl chloridc solution is wanncd to 50 on ~ watcr bath and ti1C nickcl mc.~o-octacthylp ~ yl i solution is adtlcd dropwisc tilcrcto; thc rcsul~ing rcaction mixturc is mainlaincd a~ a tcmpcralurc of 50-55 and slirrcd for 15 minutcs and is thc1l warmcd for an addilional 30 minutcs. A 150 mL portion of a saturatcd aqucous solution of sodium acctatc is lhcn addcd to ~hc rcac~ion mix~urc aftcr which stirring and hcating arc continued for an additional ~wo hours. Thc organic and thc aqucous laycrs arc scpara~cd; Ihc aqucous layer is cxtractcd twicc wilh 100 mL oortions of diclhyl cthcr; and Ihc ethcr cxtrac~s arc addcd ~o Ihe organic layer. lllc organic solvenls arc thcn rcmovcd undcr rcduccd prcssurc and Ihc rcsiduc is dissolvcd in chloroform and chromatographcd on an alumina column (3 x 30 cm). n~c product is crystallizcd from a mixed chloroform-ethanol solvcnt as long rcd fcllcd ncedlcs.
Thc nickcl oclaclhyl~ ol~)h~ l was produccd from a solulion in 50 mL
Xylcnc of 506 mg nickcl mcso-fonl1yloclac~hylporpl1yril1 and 1.024g (carbc~hoxymclhylcnc)-triphcnyl phosphoranc.
1 roduclion of nickcl mc.~o -(13-cthoxycarbonYlvinvl) octaethYIvv~ VhY~
Thc xylcnc solution of nickcl meso-fonnyloctacthylporphyrin and (carbcthoxymcthylcnc)-triphenyl phosphoranc was hcatcd undcr reflux for 18 hours. Thc solution was coolcd; Ihc xylcnc was rcmovcd 'n vact o;
and thc solid which rcmaincd was dissolvcd in Illc miniml-rn amount of dichloromcthanc and chromatographcd on silica. A minor fraction of nickcl mcso-formyloctacthylpol~-lly-;ll and a major rcd fraction wcre I~OY. .~d.
The sol~cnt was rcmoved from the red fraclion; Ihc solid which remained was recrystallized from a solvcnt cu.llpo~cd of cqual parts by volume of dichlorotnelllane and mc~h~nol yiclding 455 mg small brown ncc~llcs.
Thc product was idcnlificd by nuclcar magnclic l-,. unanCC as nickcl meso-(B-clllo~y~lbonylvinyl) octaethyl-pO~I~l,ylill.
P~otluction ofmeso-[13-(ctho~ Yud~b ",~I)vinYI~ octacthvlporphyrin Asolution of 621 mg of nickcl meso-(13-cthoxycarbonylvinyl) octaethylpol~l,ylhl in 10 mL concentraled sulfuric acid is allowcd to stand at room tcmperalurc of about 22- for 2 hours. Additions of 100mL
dichloromcthane and cnough saluralcd sodium bicarbona~c ~o nculralize Ihc rcaclion mixlure are thcn madc.
The organic layer is Ihcn collcaed washcd and dricd and thc solvcnl is removcd. n~c crude product is purificd by crystallizaion from dichloromcth tnl-melha11ol.
Produclinn of meso-~3-(hydroxy)pro~cnyll octacll,~ll)ulvh~
A solution of 200 mg meso-[13-(ethoxycarbûnyl)vinyl 1 oct tethylporphyrin in 100 mL dry ~etrahydrofuran i5 coolcd undcr nilrogc1l lo -78- using an acctone/dry icc ball-. An cxccss of diisobulyl aluminum l-rdridc in dry tetrahydrofuran (20 mL of lM solu~ion) is tllen addcd followcd by onc hour of stirring at reduccd tcmpcralurc. Additions are then madc of 100 mL watcr 100 mL of a 10 pcrcent aqueous solution of sodium hydroxidc and 200 mL walcr and thc rcsulting mixturc is stirrcd ror 30 minulcs al room II .~P ~.IIU~C of about 2~3853~-W094/00118 PCl`/US93/05727 2~. Thc organic laycr i5 thcn cnllccletl, washcd and dricd, and the solvcn~ is rcmovcd undcr vacuum. Thc crudc product is purificd by crystalli%a~ion from dichloromcthanc-mcthanol.
Production of octaclhylbcn7l-chl0rin Asolulionofl50mgmcso-[3-(hydroxy)propcnyl] octactlnylpulyllylhl in3mLconccnlratcdsulfuricacid is kcpt at room tcmpcraturc for 5 minutc~s, artcr which timc a 20 mL portion of dichloromcthanc is addcd to thc solution. Saturatcd aqucous sodium bicarbonatc is thcn addcd until thc rcaction mi%turc is ncutral. Tllc organic laycr is thcn collcctcd, washcd and dricd, and thc solvcnt is rcmovcd. Thc crudc product was purified by crystallizaîion from dichloromcthanc-mcthallol which con~ained 9V/V mc~hq.lnl.
Production of Ni oc~acthYlb~n7r~chlorin A solution is prcparcd by di.ssolving 20 mg octacthyl bcnzochlorin hl a mixcd solvcnt composcd of 15 mL dichloromcthanc and 5 mL mcthanol and a 100 mg portion of nickel acctate is added to the solution; thc mixturc which rcsults is rcfluxcd for about 2 hours until thc electronic spectrum of the reaction mixture indicates that chclation is complcte. Thc rcaction mixturc is thcn U~IC~ dtcd to 7 mL and allowed to cool to room tC~ dtlllC of about 22. Prûduct which prccipitates is IC- uvc~;d by filtration, dissolved in a mixed solvent c~,l..l,uaed nf S mL and 2 mL mcthanol, and recrystallizcd, yielding the Ni complex of octacthylbenzochlorin.
Production of Cu octacthvlbcn7nchlorin A solution was preparcd by dissolving 20 mg octacthyl bcnzochlorin (Morgan et al., "Observations on the Synthesis and in vivo Photodynamic Activity of some Bcnzochlorins", I'lwtochcmis~ry and Pho~obiology Vol. 55, No. 1, pagcs 133-13fi, 1992) in a mixed solvcnt ~o~lyosc.d of 15 mL dichlo.ù~ l.d..c and S mL
mrth~nl and a 100 mg portion of copper acctatc was addcd to the solution; the mixture which resultcd was rclluxcd for about 2 hours until the electronic spcctrum of the reaction mixture indicated that chelation was comrl~t~P The reaction mixture was then co..L...t.~ted to 7 mL and allowed to cool to room t~. .p~n~ ; of about 22. Product which precipitaled was recovered by filtration, dissolved in a mixed solvent ~-----l-u-~d of S mL dichlorome~hqnP and 2 mL me~hqrtr)l, and rccrystallized, yielding the Cu complex of octaethyllJ~..,u. l.lorin (yield, 90 percent of thcory).

The ~ ccJule of Example 1 can be uscd to produce benzochlorinimine aucu-Jil-g to the invcntion from Ni octaetl.ylb~ uchlorin and from other benzochlorins which can be produccd by the mcthod of Example A
from the ~ ol~ling pul~vhy~hls (note that Ihe identities of Rl through R8 in the Ni benzochlorins of the tiull are the same as in the po-l,l.yli.. starting material for Example A; this is generally truc). Pull/h~ s having an apl,.u~iatc structure to produce benzochlorinimine metal compl~PY~c accu~di..g to the instant invention (formula setforth abovc, and identificd by Iegend wherc Rll is hyll~u~,..l) are eithcr known or can be p~uJu~ cd by known reactions from thc rcquisite dipyrrolic intrrmcdi~tcs~ e.g., dil,~ h~ c and dipyllu~ h-~nrc, which, in tum are either known or can bc synthesizcd from the requisile pyrroles. Thc requisite pyrroles, if not available, can be syllthc~sizcd by the classical Knorr Rcaction and variations, and by - other known reactions, and can be manipulalcd and transformcd (sce, for examplc, David Dolphin, ~he l'~,/~,hr,ins, Volumc 1, Structurc and Synthcsis, Part A, Acadcmic Prcss, Ncw York, San rldn~ uu and London, 1978, pagcs 101-163). Thc pyrrolcs havc thc rollowillg struclurc:

WO9J/00118 2138538 ~: ~ PCI/US93/057~7~


where A can be H, CH~, an ester, a nitrile, a ~yd"ovinyl or an amide group, D can bc H, an e~stcr, a nitrile, a ~ydno~hlyl or an amidc group and B and C arc substitucnts which appear in the ultimatc po",hy,i,., frequcntly lower alkyl groups, particularly mclhyl and ethyl.
Dipyrrolic inlcrmcdiates, c.g., dipyrromclllanc~ and dipyrromethcncs, can bc synthesized from pyrroles, and can be eonvel1cd to porphyrins by known reactions: some porphyrins can bc synthesized directly from pyrroles (see, ror example, David Dolphin, supra, ~ages 85-100 and 163-234). Dipyrromethanes and di~ lu~ thenes have the following structures.


Dipyrome~hanes 2 1 3 8 5 3 g WO 94/00118 - PCI`/US93/05727 C H E

B~ = ~F

~bN ~

By way of B r e e x a m p I e, Dipyrromethenes "Octamethylpor phyTin" can be synthesized by healing 3,4-dimelhylpyrTole (foregoing slrueture, where A is HOOC, B and C
are CH3 and D is CH20H) at 160-170' and "Octaetl,yli,o.,ul,y-h~" can be syn~heci7ed by heating 3,4-diethylpyrTole, where A is HOOC, B and C are CHzCH3 and 1~ is CHlOH. rull~hylilJs can also be produced fTom dip~llu...~ snf C by way oî an aldehyde coupling reaetion, a formie aeid or orthoformate ester c~."J~ ion by the "dialdehyde synthesis" or by the Vilsmeier pyrrokelone synthe.sis, and fTom dip.~u~. thcnrc by ~IC Fischer synthesis, or by reaction with dipyrromelhanes. llle porphyrins that are ~)lu.luccd have the following structure wllere R is hydrogen and R1 through R4 and R5 through R8 have the same m-~ning,C as B, C, E and F in the di,u~".r..r~hsnr and ~ u~ thene starting materials when the JL,~lillb are synthesi7rd from these ylu~,u~ul~.
_~ ~3 R1<~ R~
NH N~<

R3~ R6 In oeta...~lhrl~,u.iu},y,i,. and octaetl-ylpu-i,hy,il-, R is hydrogcn and Rl thlough R8 are methyl in the former and ethyl in the latter.
Ni Octaetl.rl~,u,~,hr,i", Ni Octametl-yll~ul~llylill and Ni complexes of other known POI~JIIYI;IIS and of h~ ,b which can be syntheci7rd by the ~-uccdu-~ bu."...a,i~ d above produce, when used in the tJIuccdult;
of Example A, Ni ul"plu~- s of benzochlorins having the strueture of Fig. 1, supra, where M is Ni and R10, R11, R12 and R14 are Lrdlug~.l. These benzochlorins, when used in the ~-,uccd",~ of Example 1, produce Cu or Ni benzoehlu~illil-li--cs acuo,dillg to the invention having the strueture set forth above, where R11 is hyd~ug~ l~. The benzoehlorins of Fig. 1 ean bc reaeted with the Vilsmeier r-:agent to introduee a formyl group as R1û. The formyl group, aftcr separation of the isomers, if ncc~bd,y, can be reduced to CH3, or ean be 2138538 . - .
W094/00118 PCI`/US93/05727 rcduccd lo CH~OH or convcrtcd to an oximc group, which can (hcn bc convcrtcd to a cvano group, whi--tum, can bc convcncd to an amidc. ~hc formyl group can aiso bc rcactcd wilh WiZtig rcagcnts to givc alkyl, alkcnyi or calboxy sidc chains or to introduce thc prcviousiy idcntificd substitucnts which havc an aminc or an alcoholic OH funclion in thc R9 or in thc R10 position.
Thc i IUCC iUI~: of Examplc 1, supra, produccs Cu Bcn?ocl1loriniminc I rrom Cu oc~actl1yl bcn70cl110rin.
Whilc octacthyl bcnzochlorin can bc produccd from mcso~ hydroxyvinyl)-octacthyl ~o,l,h~,in, i~ is not possiblc, so far as is known, to producc Ihc uncomplcxed bcnzochloriniminc co"-,~},onding with Cu ~cnzochloriniminc I from oc~actllyl bcn~.ochloril~ ccordingly, ~o producc ~hc bcn~.ochlorinimincs ac~ol iing to thc inslant invcntion (~Iru~ ,s sct forth abovc) the co~ ,o.~ding Ni or Cu bcnzochlorinimincs should be produced by the mcthod of Example 1, and thc Ni or Cu sbould thcn bc rcmovcd by acid trcatmcnt. Acid treatmcnt to removc mctals from porphyrins is disclosed b~ Viccntc ct al., supra, and to remove Ni from Ni Octaethyl Bcnzochlorin is illustra~cd in Examplc ~, bclow.
Example B
A 40 mg portion of Ni Octacthyl Bcnzochlorin was s~irrcd for ~h hours in 4 mL conccntrated (98 pcrccnt) sulfuric acid. n~e reaction mixturc which resultcd wns pourcd onto icc, ncutralized with sodium l-~d-~,g"l carbonatc, and cxtractcd ui(h dichlorome~hanc. Two rcaction products (20 mg of each) wcre rccovcrcd by chromatogtaphin~ thc cxtract on silica gcl. Onc of thc products was idcntificd as Octaethyl Bcnzochlorin, whilc thc othcr was idcntificd as thc sulfonatc Ihcrcof. n~c sulfol-a~c was found to havc thc structure of Fig. 2, supra, whcrc R14 is SO~Na, and is attachcd cilhcr to the availablc carbon ncarcr R2 or to thc available carbon ncarcr R3, probably Ihc formcr. Thc octaelhyl benzochlorin was crystallizcd from dichlornrncth~n~ con~aining 2 V/v mc~hanol, whilc thc octaetl1yl bcn70cl110rin sulfonate W:1S crystallized from dichloromethanc. Lambda m~lrimnn1, U V, was 657 nm for both products. n~c SO3Na group can bc converted to SO3H by acidifyh1g thc sulfonatc, and thc hydrogcn of thc S03i1 group can bc convcltcd to othcr cations by ncutralizing with othcr bascs.
nhe Ni and othcr mctal complcxcs of tl~ octaethyl bcnzochlorin and of Ihc octacthyl bcnzoclllorin sulfonatc can bc produced from octacthvl bcm~ochlorin and from octacthyl bcnzochlorin sulfonate, a suitablc proccdure for producing thc Ni complcx bcing dcscribcd bclow as Examplc C.
Examplc C
Production ot Ni octacthyl bcnzochlorin sulfonate A solution is prcparcd by dissolving 20 mg oclaclhyl bcnzochlorin sulfonate in a mixcd solvcnt composed of 15 mL dichloromethanc and 5 mL mctllal1ol and a 100 mg portion of nickcl acclatc is addcd to thc solution;
thc mixturc which rcsulls is rcnuxccl for about 2 hollrs until thc clcctronic spcctrum of thc rcaction mixturc indic~tcs that chclation is completc. n~c rcaction mixturc is thcn conccntratcd to 7 mL and allowcd to cool to room ~empcraturc of abou~ 22. I roduct whic}l prccipilatcs is rccovcrcd by filtration, dissolvcd in a mixcd solvcnt ~u~llpos~,d of 5 mL dichloromctl1a11c and 2 mL mcthanol, and recrystallizcd, yiclding thc Ni complex of octaethylbenzochlorin sulfonatc, which has thc structurc of ~ig. 1, supra, whcrc R1 through R8 are ethyl, R14 is SO,H, R10, R11 and R12 are hydrogcn and M is ~i. Thc plUCc iUI; of Examplc 1 can then bc used to convcrt thc Ni complcx of octac~hylbcnzochlorin sulronate lo a bcnzochloriniminc according to the invenlion having thc structurc se~ forth abovc, and dcsignEItcd by Icgcnd, whcrc Rl tilrougl1 R8 are ctllyl, R11 is SO~H, thc idcntities of R and R dcpcnd on thc dialkyl formamide uscd, and ~ is Cl.

WO94tO0118 PCI'/US93~05727 The mcthod of Examplc C, supra, Gan be used to produce mctal complcxcs of bcnzochloriniminc~s according to thc h~vcntion. Spccifically, an cguivalent amount of a bcn7.0chloriniminc accordh~g to thc invention can be substituted for thc octacthyl bcnzochloriniminc, or coppcr acctatc can bc substitutcd for thc nickcl acctate, or both substitutionc can be madc. In this manner, benzochlorinimine mctal complexc~s having the structure indicatcd by Ihc roregoh~g ~ormula wherc M is cither Cu or Ni can bc produccd from ben~ochlorinimine~s having the structure indiealed by the foregoing formula. Iron complexes can bc produced by the method of Example C by substituting FcCI~ for the nickcl acctate, in which case M in the formula is ~e(CI). NiC12 ean also be so substiluted, in which ease M in the formula is Ni(O~)2. Olher benzochluiil,i",i"c metal cu-l",lcx~ can also bc madc from thc cu-~ ,u,.ding bcnzochlo,h~i",i,.cs by the methods disclosed in "Morgan et al. IIn, U.S. patent No. 4,877,872, Octobcr 31, 1989 (scc column 32, line 56 to column 34, line 7) for the preparalion of purpurin and ehlorin metal complexes; all that is ne~ uy is to sul,~ ulc an equivalcnt amount of the bcnzochl~"i"i"~i..c mctal complex for thc purpurin or ehlorin.
Similarly, porphyriniminc nickel complexcs, chlorinimine nickcl comrl~c~ bacteriochlorinime niekel enmpiex~c.c ehlorophyllimine nickel ~ pleaf~ bacterioehlorophylliminc niekel eoIDplexes, ~,u-l,u-i"i,nine nickel eomplexes, redueed pu,l,u,i"i."inc niekel eomplexes, verdinimine nickel eomplcxe~s, and Diels Alder Adduct Imine nickcl complexes, and isobacterioehlorin metal eomplexes wn be produeed by the method of Examplc 1, by substituling for the Ni Oetaethyl T3rn7Oehlorjn starting matcrial an equivalenl amount of the niekel eomplex of an appropriate po",l~ , ehlorin, baeteriochlorin, chlorophyll, baeterioehlorophyll, purpurin, reduced purpurin, verdin, Diels Alder adduct, or isobaetcrioehlorine to produec the desired imine. Thc imines can then be produecd from the imine metal eomrlexrs by the method of Example B, and other imine metal COIIIPI~ A~ ean then be produced by the method of Example C and the variations ~icc--cced abovc. n~c required pv~yll~ starting m~ n~lc are all either available or can be uludu- -d by the melhods dicrllcced above. The required purpurin metal eomplex and redueed purpurin metal eomplex starting materials ean all be ~,lu.lue~.d by the methods .1 ~ lo~d in "Mùrgan ct al. III" (U.S. patent No. 5,051,415, granted , wherc the reduced ~JUI~)Ulill5 arc named as "ehlorins"). Thc rcquircd Dicls Aldcr Adduets ean all bc produced by the method of "Lcvy et al." (IJ.S. patent No. 4,883,790, grantcd No~rc."l,c. 28, 1989). Thc rcguircd verdin metal complex starting m~tcrj:llc can all bc produccd by thc mcthod of Morgan et al. (supra). n~c requircd ehlorin, baterioehlorin, ehlorophyll, isoba~ io- hlorilI, or bactcriochlorophyll starting material ean be produeed by the mcthods ~licclosed in David Dolphin, 'rl~e l~u~ y irL'i, Volumc 11, Acadcmic Press, New York, San F ~n. i;,-;u and London, 1978, (see pages 1-85 and 131-156). The required bacteriochlorin Diels Alder Adduets to produce Imines 1, Il and III thereof can be produced as described in Morgan et al., J. A~ea'. Chem, 1990-1991, Volumc 34, No. 7, pages 2126-2133, and thc required starting matcrials to producc the Chlu.i--i-.,i--~ and metal ~ . c, thc familics of c.,.,.puu..d, which arc de~signatcd Isobacteriochlorinimine I and Isobac~riorhlorilIimine llandthcmetalcomplcxesthercorandtheramilicsor~u~ ,c,u..l~,whicharedesignated - ba~ ,.io. hlorilIiminc and the mctal complcx~s thereof, which includc a CH2 group or O which, in cithcr case, is bonded to a carbon of the pyrrole ring by a double bond, can all be produced by l~uc~,du~,s which are disclosed in the literature. A dimer ._u~-~pos~ d of one moleculc of any of the imines or imine metal complexes of the instant invention and a second molcculc of the samc or a difrerent imine or imine metal complex of the instant invcntion or thc parcnt Ix~rphyrin, chlorin, bactcriochlorin, chlorophyll, bactcriochlorophyll, purpurin, 2138538i PCI`/US93/05727 rcduccd purpurin, vcrdhl, Dicls Aldcr adduct. bcnzoclllorill or a mctal complcx of onc of thc forcgoin~n bc produccd by thc mcthod disclosc I in Morgan ct al. Il (supra). Such dimcrs arc produc:s of rcaction bctwccn a CO2R, CH,CO2R or CH2C~i2CO2R gloup or onc of thc imhlc~s or iminc mclal complcxcs alld an amino nitrogcn or an alcoholic OH group or thc othcr- of thc imincs or imhlc mctal coml~lrx~s 13y suitablc substitution of slarting m;ltcrials, and ~hc syntllGsis or polphyrill and othcr starting matcrials as di~c~- scd abovc, ir nccc~ thc proccdurcs or Examplcs A and 1 can bc uscd to pro lucc Ni bcnwchlorins and othcr Ni imh~cs according ~o Ihc invell(ion having thc mctal complcx :~tlU tUlUs sct forth above, whcrc M
is Ni, R and R G'lll bc thc samc or diffcrcnt and cach is hydrogcn or an alkyl group having from 1 to 4 carbon atoms, and cach of Rl through R11 is:
H or CHO, an alkyl group othcr tha n t-L~utyl having from 1 to ~ carbon atoms, an alkylcnc group having from 2 to 4 carbon atoms, a group havins ~hc fonnula R~N(R4)2 whcrc R3 is a bivalcnt aliphatic hydrocarbon radical having rrom 1 to 4 cctrbon atoms, whcrcin any carbon to carbon bond is citller n singlc or a doublc bond, and not morc ~han onc is a doublc bond; R~ is hydrogcn or an alkyl radical having from 1 to 2 carbon atoms and thc two R, groups can bc ~hc samc or diffcrcnt, a group having thc formula R3N(R5)3 A whcre R~ i~ca bivalcnt aliphatic hyJIuc."l~oll radical havhlg from 1 to 4 carbon atotns, whcrcin any carbon to carbon bond is cithcr a shlglc or a doublc bon 1, and not more tllan onc is a double bond; A is a physiologically acccptable anion and R5 is an alkyl group having from 1 to 2 carbon atoms and thc thrce Rs groups can hc thc same or diffcrcnt, a group having ~hc formula R~OH whcrc R? is a bivalcnt aliphatic hydluLdll on radical having from 1 to 4 carbon atoms, whcrcin any carbon to carbon bond is cithcr a singlc or a douole bond, and not more than one is a double bond, or COlR, CH2CO2R or CH2CH2CO,R vhcrc R is H, or an alkyl group othcr than t-butyl having from one to four carbon atoms.
Bcn~.ochlorinimincs a~co,di,lg lo tllc h~vcntion which havc Ihc slruclurc of thc forcgoing formula can bc produccd as li cl~ccd abovc by rcmoving tltc Cu or Ni from thc col, ;.~o"ding Cu or Ni bcnzochlorinimincs, and thosc bcnzocnlorinimincs can bc mct~ cd as discusscd abovc to producc bcnzochloriniminc mctal co~nrleYcs wherc M ~ a mctal cation that is complcxcd Wilh two of thc nitrogens of thc bcnzochloriniminc and is any of thosc mctals discloscd above. Similarly, othcr imines a.-ulJillg to thc jllvcntion can bc ~>luJuccd by rcmûving Ni from thc u~ Jo~ding Ni imincs, and the imines can be mf~t~ d as ~ c~ cd abovc to producc iminc mctal complcxcs whcre M ~ ,5 a mctal calion that is .o".p'~ ~ d with two Or the nitrogcns of thc imine and i5 any of IIIOSC metals discloscd above.
An anion cxchangc rcsin can be uscd lo introducc any dcsircd anion (A- in lhe foregoing fonnulas) into an iminc or iminc mctal complex according to thc invcntion. n~c anion cxcilange resin is mercly l ~ dtcd with a salt or acid which has the dcsircd anion, and thc iminc or iminc mctal salt is pourcd through a column packcd with the aniûn cxchangc rcsin.
The production of Ni Benzochloriniminc I solutions in the spccific non-ionic solubilizer that is available undcr thc drsiE~ion CREMOPHOR EL, and thc produc~ion Or cmulsions Or such solutions with 94/00118 2 1 3 8 5 3 g PCr/US93/05727 /~ 1,2-propanediol and salinc solution is (lcscribcd above, ~s i5 thc usc of such solutions to dctcct and trcat tumors. It will bc apprcciatcd that bcn~ochlorinimincs and othcr imincs according to thc invcntion nnd thcir mctal complcxes can bc dissolvcd hl othcr llt)ll-iOlliC solubilizcrs and that thc solutions can bc uscd to producc cmulsions that can bc administratcd intravcnously For example, othcr rcaction producls of cthylcnc oxidc and castor oil can bc so uscd, as can rcaction products of ethylcnc, propylcnc and othcr similar oxidcs with olhcr fatty acids and thc rcaction products of propylcnc and othcr similar oxidcs with Gastor oil. Similarly, glycols olher than 1,2-propancdiol can be uscd in producing thc cmulsions for intravcnous administration, or thc glycol can be omittcd, particularly if thc solubili7cr is prcparcd to havc a lowcr viscosity and grcatcr compatibility with watcr, by co,,)~..,i;,u,, with thc solubilizcr that is availablc under thc dcsignation CI~EMOI'HOR EL. It is DCC~dly only that thc .solution or cmulsion bc onc whicll is physiologically accçpt~kle and of a suitablc concentration, or dilutablc to a suitablc conccntration, for intravcnous administration or for local administration, should that bc desirablc. An indcfinitcly large numbcr of such solutions and rrnol~ionc will be apparcnt to those skilled in thc rclcvant art from thc foregoing Spcciric disclosurc. Similarly, thc aqucous phasc necd not be 0.9 percent or any othcr cu.,~utldtion of sodium chloride. Such salinc is prcscntly favored for,ol,~
aJ.~ ...tion, but othcr agucous phascs can also be uscd, so long as thc cntire composition is physiologically ~cceptnblc for intravcnous n~ln~inictration and, in fact, othcr aqucous phascs may subscqucntly bc favored.
Indced, othcr aqucous phascs or organic phascs may bc favorcd for local administration.
Dosages ranging from 3.5 to 7 mg pcr kg of body weight wcrc uscd in the in vivo tJ~u~.clul~ .1- .u~;h~d abovc. It has bccn dctcrmincd only that tllc biological Uul15C~U.,.~ .5 dcscribcd above were caused by the dosagcs ariminictrrcd~ not that any dosagc rcportcd is cithcr a n-inim--m or a mnYimllm It will bc apprcciatcd, therefore, that it is nc ~ dly only to usc an cffcctivc amount of a bcnzochlorin or mctal complcx a~u~"di..g to the invcntion in thc rictçctiQn and trcatmcnt of tumors, prcferably as small a dosagc as possiblc, and that the exact dosagc can be determincd hy routine c~ ntation. While systcmic admi..;~-dtion has bcen dcscribed abovc, crccirirAlly i"t,.,~."ou " it will also be apprcciatcd that local atlminislration will be suitablc, at least in somc inc-nrtct~c Illumination of tumors containing a bcnzochloriniminc or anothcr iminc or a mctal complcx in accor-ldnce with thc instanl invcntion can bc a surfacc illumh~ation witll a convcntional sourcc for pulscd light of a suitable wavelcngth, fiu~u~.n~y and intcnsity, as dcscribcd above, or can bc a surfacc illumination with a laser. n~c illo~rtin~tion can also bc into thc body of a tumor, for cxamplc through optical fil)crs inserted thcreinto.
The benzochlorinimin~c othcr imincs, mctal complcxcs, and dimcrs of thc prcsent invcntion can bc uscd as ~I;c, ~ d above for the of tumors, and thcy can also bc used for thc dissolution of plaques in blood vessels, and for the t,~ atl..c..t of topical conditions such as rcorj~sic fungal infcctions, acne, athletcs foot, warts, papilloma and for thc stcrili7ation of blood for t-d--sfu~ions, as will now bc explained. While the i..t,.,.~ ..u, injection of the bcnzochlorins and thc likc has bcen dc~scribcd, thcy can also be injected subcot~n~oncly~ ;.. t. J~ rly or intrapcritoncally. Dosagcs can vary widcly, but thc in vivo test data rcported above indicate that thc illlld~,.,.lOUs arhninictration of up to 7 mg pcr kg of body wcight is safc. Thc bcnzochlorinimincs and thc likc can be formulatcd in lolions~ suspcnsions or pastes for localized trcatmcnt, e.g., of superficial tumors or skin disordcrs.

WO 94/00118 -- PCI/US93/05727~
Various changcs and modirication can l~c madc from Ihc spccific dctails of (hc invcnlion as dcsc~d abovc witout dcparting from ~hc spirit and scopc thcrcof as dcfincd in thc appcndcd claims~

Claims (15)

1. As a composition of matter, a purified imine of a porphyrin, a chlorin, a bacteriochlorin, a chlorophyll, a bacteriochlorophyll, a purpurin, a reduced purpurin, a verdin, a Diels Alder adduct, an isobacteriochlorin, a benzochlorin or a metal complex of one of the foregoing imines having one of the structures set forth below, and identified by legend:

Porphyrinimine Chlorinimine Chlorophyllimine Bacteriochlorophyllimine I
2. A benzochlorin metal complex as claimed in claim 1 wherein each of R9 through R11 is hydrogen, each of R1 through R8 is an alkyl group other than t-butyl having from 1 to 4 carbon atoms, and M is Sn.
3. A composition consisting essentially of a solution in a solvent of a benzochlorin having the structure of Formula III or a metal complex of a benzochlorin having the structure of Formula IV, below:

Formula III Formula IV

wherein M comprises a metal cation that is complexed with two of the nitrogens of the benzochlorin and is Cu or Fe, R1 and R2 can be the same or different and each is an alkyl group other than t-butyl having from 1 to 4 carbon atoms, and each of R1 through R11 is H or CHO
4. A solution of a benzochlorin metal complex as claimed in claim 3 wherein each of R9 through R11 is hydrogen, each of R1 through R8 is an alkyl group other than t-butyl having from 1 to 4 carbon atoms, and M is Cu or Fe.
5. An aqueous emulsion or suspension of a solution as claimed in claim 3 of a benzochlorin or a benzochlorin metal complex.
6. An aqueous emulsion or suspension of a solution as claimed in claim 4 of a benzochlorin metal complex.
7. A method for treating a human or animal patient which comprises administering an effective amount of a benzochlorin having the structure of Formula III or of a metal complex of a benzochlorin having the structure of Formula IV, below:

Formula III Formula IV

wherein M comprises a metal cation that is complexed with two of the nitrogens of the benzochlorin and is Cu or Fe, with the proviso that R11 can be SO3H or a salt thereof, and irradiating the patient with pulsed excitation at a suitable wavelength and of sufficient intensity to promote residual benzochlorin or benzochlorin metal complex in the patient to the singlet state.
8. A method as claimed in claim 7 which comprises administering a benzochlorin metal complex wherein each of R9 and R11 is hydrogen, each of R1 through R8 is an alkyl group other than t-butyl having from 1 to 4 carbon atoms, and M is copper.
9. A method of treating tumors to destroy the tumors comprising administering an effective dose of the copper complex of the imine composition claim 1.
10. A method of treating tumors by administering to an animal or human an effective dose of a copper complex of octaethyl benzochlorin imine.
11. A tumor treating imine composition that is a complex as defined in claim 1.
12. A tumor treating imine composition that is as complex as defined in claim 1 in which M is copper.
13. A light activated tumor treating imine composition using photodynamic therapy, the composition comprising a complex as defined in claim 1.
14. A light activated tumor treating composition for treating tumors with photodynamic therapy, the composition comprising a complex as defined in claim 1 in which M is Cu.
15. A light activated tumor treating composition that is a copper complex of octaethyl benzochlorin imine.
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Families Citing this family (21)

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US5744598A (en) * 1992-06-19 1998-04-28 University Of Toledo Imines of porphyrins, of porphyrin derivatives, and of related compounds, and pharmaceutical compositions containing such imines
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US5648232A (en) * 1993-01-21 1997-07-15 The Secretary Of State For Defence In Her Britannic Majesty's Government Of The United Kingdom Of Great Britain And Northern Ireland Microbiological best method and reagents
US6117369A (en) * 1998-04-28 2000-09-12 Sandia Corporation Nickel porphyrins for memory optical applications
US6703050B1 (en) 1998-09-04 2004-03-09 The Regents Of The University Of Michigan Methods and compositions for the prevention or treatment of cancer
CA2345580A1 (en) * 1998-10-05 2000-04-13 Lambda Pharmaceuticals, Inc. Photosensitizers for photodynamic applications
US6482943B1 (en) * 1999-04-30 2002-11-19 Slil Biomedical Corporation Quinones as disease therapies
US6649587B1 (en) 1999-04-30 2003-11-18 Slil Biomedical Corporation Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
AU4678300A (en) * 1999-04-30 2000-11-17 Slil Biomedical Corporation Novel polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
US20040228871A1 (en) * 1999-06-03 2004-11-18 Tayyaba Hasan Treatment and analysis of proliferative disorders
JP2004513136A (en) * 2000-11-08 2004-04-30 スリル バイオメディカル コーポレーション Useful novel polyamine analog as an anti - amino acid complex
US6462192B2 (en) * 2001-01-23 2002-10-08 Miravant Pharmaceuticals, Inc. Processes for large scale production of tetrapyrroles
WO2002095050A2 (en) * 2001-05-18 2002-11-28 University Of Maryland, College Park Trinuclear copper-based compound and ligand for nucleic acid scission and anticancer treatment
EP1531827A4 (en) * 2002-05-24 2009-07-08 Univ Michigan Copper lowering treatment of inflammatory and fibrotic diseases
US20070248689A1 (en) * 2002-05-24 2007-10-25 Regents Of The University Of Michigan Copper lowering treatment of inflammatory and fibrotic diseases
WO2004009072A2 (en) 2002-07-23 2004-01-29 The Regents Of The University Of Michigan Tetrapropylammonium tetrathiomolybdate and related compounds for anti-angiogenic therapies
IL152900D0 (en) * 2002-11-17 2003-06-24 Yeda Res & Dev Water-soluble bacteriochlorophyll derivatives and their pharmaceutical uses
US20120034155A1 (en) * 2010-08-03 2012-02-09 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Artificial cells
GB0819594D0 (en) 2008-10-24 2008-12-03 Univ Coimbrra Process
US9549928B2 (en) 2011-04-29 2017-01-24 The University Of Toledo Muscarinic agonists as enhancers of cognitive flexibility
CN103405769A (en) * 2013-03-07 2013-11-27 北京亿仁赛博医疗科技研发中心有限公司 Application of photosensitizer to preparation of virus inactivated medicines for treating diseases

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AU682149B2 (en) 1997-09-25
JPH08506566A (en) 1996-07-16
AU4635993A (en) 1994-01-24
US5424305A (en) 1995-06-13
WO1994000118A1 (en) 1994-01-06
EP0644759A1 (en) 1995-03-29
EP0644759A4 (en) 1998-04-01

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